Design, synthesis and biological evaluation of a novel class of anticancer agents: Anthracenylisoxazole lexitropsin conjugates

Xiaochun Han; Chun Li; Michael D. Mosher; Kevin C. Rider; Peiwen Zhou; Ronald L. Crawford; William Fusco; Andrzej Paszczynski; Nicholas R. Natale

doi:10.1016/j.bmc.2008.12.056

Design, synthesis and biological evaluation of a novel class of anticancer agents: Anthracenylisoxazole lexitropsin conjugates

Xiaochun Han, Chun Li, Michael D. Mosher, Kevin C. Rider, Peiwen Zhou, Ronald L. Crawford, William Fusco, Andrzej Paszczynski, Nicholas R. Natale

Research output: Contribution to journal › Article › peer-review

34 Scopus citations

Abstract

The synthesis and in vitro anti-tumor 60 cell lines screen of a novel series of anthracenyl isoxazole amides (AIMs) (While not a strict acronym, the designation AIM is in honor of the memory of Professor Albert I. Meyers.) (22-33) are described. The molecules consist of an isoxazole that pre-organizes a planar aromatic moiety and a simple amide and/or lexitropsin-oligopeptide. The new conjugate molecules were prepared via doubly activated amidation modification of Weinreb's amide formation technique, using SmCl₃ as an activating agent which produces improved yields for sterically hindered 3-aryl-4-isoxazolecarboxylic esters. The results of the National Cancer Institute's (NCI) 60 cell line screening assay show a distinct structure activity relationship (SAR), wherein a trend of the highest activity for molecules with one N-methylpyrrole peptide. Evidence consistent with a mechanism of action via the interaction of these compounds with G-quadruplex (G4) DNA and a structural based rational for the observed selectivity of the AIMs for G4 over B-DNA is presented.

Original language	English
Pages (from-to)	1671-1680
Number of pages	10
Journal	Bioorganic and Medicinal Chemistry
Volume	17
Issue number	4
DOIs	https://doi.org/10.1016/j.bmc.2008.12.056
State	Published - Feb 15 2009

Funding

N.R.N. thanks the National Institute of Neurological Disease and Stroke for Grant NS38444 and P20RR015583. We would like to thank the University of Idaho Research Council, and the National Cancer Institute for financial support. Dr. Dan Zaharevitz assisted us with the COMPARE calculation and interpretation. X.H., C.L. and K.C.R., acknowledge the Malcolm and Carol Renfrew Scholarship Endowment, University of Idaho. C.L. and K.C.R. also thank P20RR16454.

Funder number
P20RR015583, NS38444
P20RR016454

Keywords

Anthracene
Anti-tumor
G-quadruplex
Isoxazole
Pyrrole

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bmc.2008.12.056

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title = "Design, synthesis and biological evaluation of a novel class of anticancer agents: Anthracenylisoxazole lexitropsin conjugates",

abstract = "The synthesis and in vitro anti-tumor 60 cell lines screen of a novel series of anthracenyl isoxazole amides (AIMs) (While not a strict acronym, the designation AIM is in honor of the memory of Professor Albert I. Meyers.) (22-33) are described. The molecules consist of an isoxazole that pre-organizes a planar aromatic moiety and a simple amide and/or lexitropsin-oligopeptide. The new conjugate molecules were prepared via doubly activated amidation modification of Weinreb's amide formation technique, using SmCl3 as an activating agent which produces improved yields for sterically hindered 3-aryl-4-isoxazolecarboxylic esters. The results of the National Cancer Institute's (NCI) 60 cell line screening assay show a distinct structure activity relationship (SAR), wherein a trend of the highest activity for molecules with one N-methylpyrrole peptide. Evidence consistent with a mechanism of action via the interaction of these compounds with G-quadruplex (G4) DNA and a structural based rational for the observed selectivity of the AIMs for G4 over B-DNA is presented.",

keywords = "Anthracene, Anti-tumor, G-quadruplex, Isoxazole, Pyrrole",

author = "Xiaochun Han and Chun Li and Mosher, \{Michael D.\} and Rider, \{Kevin C.\} and Peiwen Zhou and Crawford, \{Ronald L.\} and William Fusco and Andrzej Paszczynski and Natale, \{Nicholas R.\}",

note = "Funding Information: N.R.N. thanks the National Institute of Neurological Disease and Stroke for Grant NS38444 and P20RR015583. We would like to thank the University of Idaho Research Council, and the National Cancer Institute for financial support. Dr. Dan Zaharevitz assisted us with the COMPARE calculation and interpretation. X.H., C.L. and K.C.R., acknowledge the Malcolm and Carol Renfrew Scholarship Endowment, University of Idaho. C.L. and K.C.R. also thank P20RR16454. ",

year = "2009",

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doi = "10.1016/j.bmc.2008.12.056",

language = "English",

volume = "17",

pages = "1671--1680",

journal = "Bioorganic and Medicinal Chemistry",

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TY - JOUR

T1 - Design, synthesis and biological evaluation of a novel class of anticancer agents

T2 - Anthracenylisoxazole lexitropsin conjugates

AU - Han, Xiaochun

AU - Li, Chun

AU - Mosher, Michael D.

AU - Rider, Kevin C.

AU - Zhou, Peiwen

AU - Crawford, Ronald L.

AU - Fusco, William

AU - Paszczynski, Andrzej

AU - Natale, Nicholas R.

N1 - Funding Information: N.R.N. thanks the National Institute of Neurological Disease and Stroke for Grant NS38444 and P20RR015583. We would like to thank the University of Idaho Research Council, and the National Cancer Institute for financial support. Dr. Dan Zaharevitz assisted us with the COMPARE calculation and interpretation. X.H., C.L. and K.C.R., acknowledge the Malcolm and Carol Renfrew Scholarship Endowment, University of Idaho. C.L. and K.C.R. also thank P20RR16454.

PY - 2009/2/15

Y1 - 2009/2/15

N2 - The synthesis and in vitro anti-tumor 60 cell lines screen of a novel series of anthracenyl isoxazole amides (AIMs) (While not a strict acronym, the designation AIM is in honor of the memory of Professor Albert I. Meyers.) (22-33) are described. The molecules consist of an isoxazole that pre-organizes a planar aromatic moiety and a simple amide and/or lexitropsin-oligopeptide. The new conjugate molecules were prepared via doubly activated amidation modification of Weinreb's amide formation technique, using SmCl3 as an activating agent which produces improved yields for sterically hindered 3-aryl-4-isoxazolecarboxylic esters. The results of the National Cancer Institute's (NCI) 60 cell line screening assay show a distinct structure activity relationship (SAR), wherein a trend of the highest activity for molecules with one N-methylpyrrole peptide. Evidence consistent with a mechanism of action via the interaction of these compounds with G-quadruplex (G4) DNA and a structural based rational for the observed selectivity of the AIMs for G4 over B-DNA is presented.

AB - The synthesis and in vitro anti-tumor 60 cell lines screen of a novel series of anthracenyl isoxazole amides (AIMs) (While not a strict acronym, the designation AIM is in honor of the memory of Professor Albert I. Meyers.) (22-33) are described. The molecules consist of an isoxazole that pre-organizes a planar aromatic moiety and a simple amide and/or lexitropsin-oligopeptide. The new conjugate molecules were prepared via doubly activated amidation modification of Weinreb's amide formation technique, using SmCl3 as an activating agent which produces improved yields for sterically hindered 3-aryl-4-isoxazolecarboxylic esters. The results of the National Cancer Institute's (NCI) 60 cell line screening assay show a distinct structure activity relationship (SAR), wherein a trend of the highest activity for molecules with one N-methylpyrrole peptide. Evidence consistent with a mechanism of action via the interaction of these compounds with G-quadruplex (G4) DNA and a structural based rational for the observed selectivity of the AIMs for G4 over B-DNA is presented.

KW - Anthracene

KW - Anti-tumor

KW - G-quadruplex

KW - Isoxazole

KW - Pyrrole

UR - https://www.scopus.com/pages/publications/60049090567

U2 - 10.1016/j.bmc.2008.12.056

DO - 10.1016/j.bmc.2008.12.056

M3 - Article

C2 - 19167892

AN - SCOPUS:60049090567

SN - 0968-0896

VL - 17

SP - 1671

EP - 1680

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

IS - 4

ER -

Design, synthesis and biological evaluation of a novel class of anticancer agents: Anthracenylisoxazole lexitropsin conjugates

Abstract

Funding

Keywords

UN SDGs

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